Claudine C. Hunault

Bioavailability of sodium nitrite from an aqueous solution in healthy adults.

Nitrate intake in humans is high through intake of vegetables such as beets, lettuce, and spinach. Nitrate itself is a compound of low toxicity but its metabolite, nitrite, formed by bacteria in the oral cavity and gastrointestinal tract, has been suspected of potential carcinogenic effects. Nitrite can induce systemic toxicity only after having been absorbed from the gastrointestinal tract. The aim of this study was to determine the absolute bioavailability of nitrite following oral administration in humans. In an open, three-way cross-over study, nine subjects received two single oral doses of sodium nitrite (0.12 and 0.06 mmol NaNO(2)/mmol Hb) and one intravenous sodium nitrite dose (0.12 mmol NaNO(2)/mmol Hb). Plasma samples were analysed to assess the nitrite levels, and pharmacokinetic parameters were calculated. Nitrate and methaemoglobin levels in plasma were also measured as oxidation of nitrite results in the formation of these two compounds. Absolute bioavailability of nitrite was 98% after oral administration of 0.12 mmol NaNO(2)/mmol Hb, and 95% after oral administration of 0.06 mmol NaNO(2)/mmol Hb. Minor adverse effects were observed after the 0.12 mmol NaNO(2)/mmol Hb oral dose. In conclusion, nitrite in solution is highly absorbed from the gastrointestinal tract and the first pass effect in the liver is low.

Cannabinoid modulations of resting state eeg theta power and working memory are correlated in humans

Object representations in working memory depend on neural firing that is phase-locked to oscillations in the theta band (4–8 Hz). Cannabis intake disrupts synchronicity of theta oscillations and interferes with memory performance. Sixteen participants smoked cigarettes containing 0.0, 29.3, 49.1, or 69.4 mg Δ9-tetrahydrocannabinol (THC) in a randomized crossover design and performed working memory and general attention tasks. Dose-dependent effects of THC were observed for resting state EEG theta and beta power, working memory (per-item search time), and attentional performance (percent errors and RT). The THC effects on EEG theta power and memory performance were correlated, whereas other EEG and behavioral effects were not. These findings confirm and extend previous results in rodents and humans, and corroborate a neurocomputational model that postulates that temporal aspects of information processing in working memory depend causally on nested oscillations in the theta and gamma (>30 Hz) bands.

Acute subjective effects after smoking joints containing up to 69 mg Δ9-tetrahydrocannabinol in recreational users: a randomized, crossover clinical trial

RationaleAn increase in the potency of the cannabis cigarettes has been observed over the past three decades.ObjectivesIn this study, we aimed to establish the impact of Δ9-tetrahydrocannabinol (THC) on the rating of subjective effects (intensity and duration of the effects), up to 23 % THC potency (69 mg THC) among recreational users.MethodsRecreational users (N = 24) smoked cannabis cigarettes with four doses of THC (placebo 29, 49 and 69 mg of THC) on four separate test days in a randomized, double-blind, placebo-controlled, crossover study. The participants filled in three different questionnaires measuring subjective effects during the exposure up to 8 h post-smoking. The ‘high’ feeling, heart rate, blood pressure and THC serum concentrations were also regularly recorded during these 8 h.ResultsTHC significantly increased the high feeling, dizziness, dry-mouthed feeling, palpitations, impaired memory and concentration, and ‘down’, ‘sedated’ and ‘anxious’ feelings. In addition, THC significantly decreased alertness, contentment and calmness. A cubic relationship was observed between ‘feeling the drug’ and ‘wanting more’. The THC-induced decrease in ‘feeling stimulated’ and increase in anxiety lasted up to 8 h post-smoking. Sedation at 8 h post-smoking was increased by a factor of 5.7 with the highest THC dose, compared to the placebo.ConclusionsThis study shows a strong effect of cannabis containing high percentages of THC on the rating of subjective effects. Regular users and forensic toxicologists should be aware that the THC-induced increase in ‘feeling sedated’ continues longer with a 69 mg THC dose than with a 29 mg THC dose.

Disposition of smoked cannabis with high Δ9-tetrahydrocannabinol content: a kinetic model.

INTRODUCTION No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC). METHODS Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0-8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. RESULTS Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax=175ng/mL, Tmax=14min, and AUC0-8h=8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose=2.8×10(-6)/mL and AUC0-8h/Dose=136×10(-6)min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose=3.4, 2.6 and 2.5×10(-6)/mL and AUC0-8h/Dose=157, 133 and 117×10(-6)min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. CONCLUSION The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%).

A case series of xylometazoline overdose in children

Introduction. Serious intoxications associated with low doses of imidazolines have been reported. Therefore, the treatment advice for children with xylometazoline overdose is usually to observe the child in the hospital, even after exposure to very low doses. Our aim was to determine the frequency of severe symptoms after xylometazoline exposure, and the systemic dose of xylometazoline below which asymptomatic children do not need to be hospitalized for observation. Methods. From May 2002 until December 2004, we prospectively collected data on all consecutive cases of xylometazoline exposure in children <6 years old reported to our poisons centre. Follow-up information was collected. The systemic dose was calculated and the frequency of severe symptoms was observed. Results. During 32 months, we included 101 cases of xylometazoline exposure in children. For 63 out of these 101 cases, follow-up information could be collected. No severe symptoms were observed after exposure to xylometazoline doses reported to be below 0.4 mg/kg (95% confidence interval: 0–6%). Conclusion. We conclude that less than 6% of children exposed to xylometazoline, at doses reported to be less than 0.4 mg/kg body weight, may develop symptoms that require hospitalization.

Lamp oil poisoning: Did the European guideline reduce the number and severity of intoxications?

Introduction. In 1997, a European guideline concerning the viscosity and surface tension of lamp oil was adopted to reduce instances and severity of lamp oil intoxications. In 2005, the Dutch National Poisons Information Centre investigated lamp oil intoxications to determine whether they differed in severity from the intoxications reported before the guideline was adopted. Methods. We compared the data prospectively collected on lamp oil intoxications reported to our center in 2005 and in 1996. Results. In 2005 and 1996, respectively 152 and 165 cases were included. The frequency of the symptoms and diagnosed pneumonitis did not differ significantly between those years. In 2005, ingestion of a transparent lamp oil seemed to be associated with a greater risk of serious respiratory symptoms than ingestion of colored oil. Conclusion. Despite the directive, frequency and severity of symptoms of lamp oil ingestions remain disturbing. Consequently, further actions concerning packaging and labeling of lamp oil, design of oil lamps, education of parents, and additions to the current guideline should be considered.

Review of acute chemical incidents as a first step in evaluating the usefulness of physiologically based pharmacokinetic models in such incidents

Abstract Context. Acute chemical incidents can have substantial public health consequences in terms of morbidity and mortality. Objective. We aimed to characterize acute chemical incidents and near-misses in the Netherlands and compare the results with previous studies. This review is a first step in evaluating whether Physiologically Based Pharmacokinetic (PBPK) models can be of value in acute chemical incidents. Material and methods. Government, regional, municipal and University Hospital Institutes involved in the management of acute chemical incidents in the Netherlands were contacted, and they provided data between 2008 and 2010 on the characteristics and consequences of the incidents. The study is a retrospective epidemiological study based on data from five institutes. Incidents involving biological agents or radiation were excluded. Results. A total of 764 reports were available which involved 722 incidents after cross-matching the different sources of data. Forty incidents were excluded, leaving 682 incidents for which information was available in accordance with the inclusion criteria. Of the 682 incidents included in this study, most occurred in non-industrial buildings (37%) or industrial sites (34%). The most frequently observed event types were loss of containment (60%) and fire (36%), leading to gas emission (54%), followed by spill of liquid or solid chemicals (36%). The chemicals involved were most often products of combustion (e.g. smoke, soot, particles, 25%) and volatile organic compounds (e.g. solvents, styrene, xylene, 23%), followed by inorganic gases (e.g. carbon monoxide, hydrogen, hydrogen sulphide, 13%). A minimum of 847 people experienced adverse health effects following exposure during a chemical incident, and 10 fatalities were reported. The most frequently reported symptoms were respiratory (27%), due to irritant chemicals. The number of incidents related to fire and the number of injured people were higher in this study than in previous studies; 49% of the injured were transported to hospital. Discussion. This study helps to identify which chemicals are frequently involved in acute chemical incidents in the Netherlands. The results will be used in future to assess whether PBPK models may be useful for risk assessment of chemicals often involved in acute chemical incidents and for which human toxicological and kinetic data are scarce.

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans

Abstract Context: No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning. Objective: Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model. Material and methods: This was a kinetic modelling study. We used a two-compartment model, with a non-systemic gastrointestinal compartment (gut lumen) and the whole body as one systemic compartment. The only data available from the literature were used to calibrate the unknown model parameters. The calibrated model was then validated by comparing its predictions with measured data from three different experimental human studies. Results: The model predicted total DMSA plasma and urine concentrations measured in three healthy volunteers after ingestion of DMSA 10 mg/kg. The model was then validated by using data from three other published studies; it predicted concentrations within a factor of two, representing inter-human variability. Conclusions: A simple kinetic model simulating the kinetics of DMSA in humans has been developed and validated. The interest of this model lies in the future potential to use it to predict blood lead concentrations in lead-poisoned patients treated with DMSA.

Methylphenidate intoxications in children and adults : Exposure circumstances and evidence-based dose threshold for pre-hospital triage

Abstract Context. Methylphenidate intoxications mostly have a relatively mild course, although serious complications can occur. Objective. We aimed to characterize methylphenidate exposures and reassess our current dose threshold for hospital referral (2 mg/kg). Methods. In a prospective follow-up study, we analysed 364 consecutive methylphenidate exposures that were reported to the Dutch Poisons Information Center. Patients and/or physicians were surveyed by telephone using standardized questionnaires. Three physicians independently scored the observed severity of the intoxication of each patient as ‘no/mild’ (observation at home) or ‘moderate/severe’ (hospital referral necessary). Results. Unintentional exposures (40%) mostly occurred at home involving the patients’ own medication or those from a family member. Compared to unintentionally exposed patients, intentionally exposed patients were exposed to relatively high methylphenidate doses (3.1 vs 1.6 mg/kg), more often used immediate release methylphenidate formulations (62 vs 34%) and more frequently had concomitant exposures (71 vs 17%). Severe symptoms like convulsions or coma were reported only in patients with concomitant exposures. Following exposure to methylphenidate only (i.e. no concomitant exposures), the most commonly reported symptoms were dry mucosa, headache, agitation, sleepiness and tachycardia. Our results show that the reported methylphenidate dose is predictive of the observed severity of the intoxication and can therefore aid in pre-hospital triage. Conclusion. We increased our current dose threshold for hospital referral from 2 to 3 mg/kg. In addition, we will refer patients at lower doses when clinical symptoms indicate the need for hospital referral. Application of this new dose threshold optimizes triage, thereby reducing unnecessary hospital referral and thus costs, without jeopardising patient safety.

Modeling the effect of succimer (DMSA; dimercaptosuccinic acid) chelation therapy in patients poisoned by lead

Abstract Context: Kinetic models could assist clinicians potentially in managing cases of lead poisoning. Several models exist that can simulate lead kinetics but none of them can predict the effect of chelation in lead poisoning. Our aim was to devise a model to predict the effect of succimer (dimercaptosuccinic acid; DMSA) chelation therapy on blood lead concentrations. Materials and methods: We integrated a two-compartment kinetic succimer model into an existing PBPK lead model and produced a Chelation Lead Therapy (CLT) model. The accuracy of the model’s predictions was assessed by simulating clinical observations in patients poisoned by lead and treated with succimer. The CLT model calculates blood lead concentrations as the sum of the background exposure and the acute or chronic lead poisoning. The latter was due either to ingestion of traditional remedies or occupational exposure to lead-polluted ambient air. The exposure duration was known. The blood lead concentrations predicted by the CLT model were compared to the measured blood lead concentrations. Results: Pre-chelation blood lead concentrations ranged between 99 and 150 μg/dL. The model was able to simulate accurately the blood lead concentrations during and after succimer treatment. The pattern of urine lead excretion was successfully predicted in some patients, while poorly predicted in others. Conclusions: Our model is able to predict blood lead concentrations after succimer therapy, at least, in situations where the duration of lead exposure is known.